Fine mapping and candidate gene analysis of a dravet syndrome modifier locus on mouse chromosome 11

Pathogenic variants in SCN1A result in a spectrum of phenotypes ranging from mild febrile seizures to Dravet syndrome, a severe infant-onset epileptic encephalopathy. Individuals with Dravet syndrome have developmental delays, elevated risk for sudden unexpected death in epilepsy (SUDEP), and have multiple seizure types that are often refractory to treatment. Although most Dravet syndrome variants arise de novo, there are cases where an SCN1A variant was inherited from mildly affected parents, as well as some individuals with de novo loss-of-function or truncation mutations that presented with milder phenotypes. This suggests that disease severity is influenced by other factors that modify expressivity of the primary mutation, which likely includes genetic modifiers. Consistent with this, the Scn1a(+/-) mouse model of Dravet syndrome exhibits strain-dependent variable phenotype severity. Scn1a(+/-) mice on the 129S6/SvEvTac (129) strain have no overt phenotype and a normal lifespan, while [C57BL/6Jx129]F1.Scn1a(+/-) mice have severe epilepsy with high rates of premature death. Low resolution genetic mapping identified several Dravet syndrome modifier (Dsm) loci responsible for the strain-dependent difference in survival of Scn1a(+/-) mice. To confirm the Dsm5 locus and refine its position, we generated interval-specific congenic strains carrying 129-derived chromosome 11 alleles on the C57BL/6J strain and localized Dsm5 to a 5.9 Mb minimal region. We then performed candidate gene analysis in the modifier region. Consideration of brain-expressed genes with expression or coding sequence differences between strains along with gene function suggested numerous strong candidates, including several protein coding genes and two miRNAs that may regulate Scn1a transcript.

Automated summary

Pathogenic variants in SCN1A gene can result in different clinical phenotypes, and the severity is influenced by other genetic modifiers. The study found that disease severity is associated with the type of mutation, mode of inheritance, and genetic modifier factors.